Dietary flavanols restore hippocampal-dependent memory in older adults with lower diet quality and lower habitual flavanol consumption.

Dietary flavanols are food constituents found in certain fruits and vegetables that have been linked to cognitive aging. Previous studies suggested that consumption of dietary flavanols might specifically be associated with the hippocampal-dependent memory component of cognitive aging and that memory benefits of a flavanol intervention might depend on habitual diet quality. Here, we tested these hypotheses in the context of a large-scale study of 3,562 older adults, who were randomly assigned to a 3-y intervention of cocoa extract (500 mg of cocoa flavanols per day) or a placebo [(COcoa Supplement and Multivitamin Outcomes Study) COSMOS-Web, NCT04582617]. Using the alternative Healthy Eating Index in all participants and a urine-based biomarker of flavanol intake in a subset of participants [n = 1,361], we show that habitual flavanol consumption and diet quality at baseline are positively and selectively correlated with hippocampal-dependent memory. While the prespecified primary end point testing for an intervention-related improvement in memory in all participants after 1 y was not statistically significant, the flavanol intervention restored memory among participants in lower tertiles of habitual diet quality or habitual flavanol consumption. Increases in the flavanol biomarker over the course of the trial were associated with improving memory. Collectively, our results allow dietary flavanols to be considered in the context of a depletion-repletion paradigm and suggest that low flavanol consumption can act as a driver of the hippocampal-dependent component of cognitive aging.

A Nutrigenetic Update on CETP Gene-Diet Interactions on Lipid-Related Outcomes.

PURPOSE OF REVIEW: An abnormal lipid profile is considered a main risk factor for cardiovascular diseases and evidence suggests that single nucleotide polymorphisms (SNPs) in the cholesteryl ester transfer protein (CETP) gene contribute to variations in lipid levels in response to dietary intake. The objective of this review was to identify and discuss nutrigenetic studies assessing the interactions between CETP SNPs and dietary factors on blood lipids. RECENT FINDINGS: Relevant articles were obtained through a literature search of PubMed and Google Scholar through to July 2021. An article was included if it examined an interaction between CETP SNPs and dietary factors on blood lipids. From 49 eligible nutrigenetic studies, 27 studies reported significant interactions between 8 CETP SNPs and 17 dietary factors on blood lipids in 18 ethnicities. The discrepancies in the study findings could be attributed to genetic heterogeneity, and differences in sample size, study design, lifestyle and measurement of dietary intake. The most extensively studied ethnicities were those of Caucasian populations and majority of the studies reported an interaction with dietary fat intake. The rs708272 (TaqIB) was the most widely studied CETP SNP, where 'B1' allele was associated with higher CETP activity, resulting in lower high-density lipoprotein cholesterol and higher serum triglycerides under the influence of high dietary fat intake. Overall, the findings suggest that CETP SNPs might alter blood lipid profiles by modifying responses to diet, but further large studies in multiple ethnic groups are warranted to identify individuals at risk of adverse lipid response to diet.

Gut microbiota composition in relation to intake of added sugar, sugar-sweetened beverages and artificially sweetened beverages in the Malmö Offspring Study.

PURPOSE: It has been suggested that a high intake of sugar or sweeteners may result in an unfavorable microbiota composition; however, evidence is lacking. Hence, in this exploratory epidemiological study, we aim to examine if intake of added sugar, sugar-sweetened beverages (SSBs) or artificially sweetened beverages (ASBs) associate with the gut microbiota composition. METHODS: Participants (18-70 years) in the Malmö Offspring Study have provided blood, urine, and fecal samples and completed both web-based 4 day food records and short food frequency questionnaires. The gut microbiota was assessed by 16S rRNA sequencing, processed in QIIME and matched to Greengenes (v.13.8), giving 64 included genera after filtering. Intake of added sugar (n = 1371) (also supported by the overnight urinary sugar biomarker in a subgroup n = 577), SSBs (n = 1086) and ASBs (n = 1085) were examined as exposures in negative binomial regressions. RESULTS: Various genera nominally associated with intake of added sugar, SSBs, and ASBs. Only the negative association between SSB intake and Lachnobacterium remained significant after multiple testing correction. A positive association between SSB intake and the Firmicutes:Bacteroidetes ratio was also observed. CONCLUSION: In this wide population, the cross-sectional associations between added sugar and sweet beverage intake and the gut microbiota are modest, but the results suggest that SSB intake is associated negatively with the genus Lachnobacterium and positively with the Firmicutes:Bacteroidetes ratio. Larger studies, preferably using metagenomic sequencing, are needed to further evaluate if a link exists between intake of sugars and sweeteners and the human gut microbiota.

Oat bran, but not its isolated bioactive ß-glucans or polyphenols, have a bifidogenic effect in an in vitro fermentation model of the gut microbiota.

Wholegrain oats are known to modulate the human gut microbiota and have prebiotic properties (increase the growth of some health-promoting bacterial genera within the colon). Research to date mainly attributes these effects to the fibre content; however, oat is also a rich dietary source of polyphenols, which may contribute to the positive modulation of gut microbiota. In vitro anaerobic batch-culture experiments were performed over 24 h to evaluate the impact of two different doses (1 and 3 % (w/v)) of oat bran, matched concentrations of ß-glucan extract or polyphenol mix, on the human faecal microbiota composition using 16S RNA gene sequencing and SCFA analysis. Supplementation with oats increased the abundance of Proteobacteria (P <0·01) at 10 h, Bacteroidetes (P <0·05) at 24 h and concentrations of acetic and propionic acid increased at 10 and 24 h compared with the NC. Fermentation of the 1 % (w/v) oat bran resulted in significant increase in SCFA production at 24 h (86 (sd 27) v. 28 (sd 5) mm; P <0·05) and a bifidogenic effect, increasing the relative abundance of Bifidobacterium unassigned at 10 h and Bifidobacterium adolescentis (P <0·05) at 10 and 24 h compared with NC. Considering the ß-glucan treatment induced an increase in the phylum Bacteroidetes at 24 h, it explains the Bacteriodetes effects of oats as a food matrix. The polyphenol mix induced an increase in Enterobacteriaceae family at 24 h. In conclusion, in this study, we found that oats increased bifidobacteria, acetic acid and propionic acid, and this is mediated by the synergy of all oat compounds within the complex food matrix, rather than its main bioactive ß-glucan or polyphenols. Thus, oats as a whole food led to the greatest impact on the microbiota.

Key bioactive reaction products of the NO/H2S interaction are S/N-hybrid species, polysulfides, and nitroxyl.

Experimental evidence suggests that nitric oxide (NO) and hydrogen sulfide (H2S) signaling pathways are intimately intertwined, with mutual attenuation or potentiation of biological responses in the cardiovascular system and elsewhere. The chemical basis of this interaction is elusive. Moreover, polysulfides recently emerged as potential mediators of H2S/sulfide signaling, but their biosynthesis and relationship to NO remain enigmatic. We sought to characterize the nature, chemical biology, and bioactivity of key reaction products formed in the NO/sulfide system. At physiological pH, we find that NO and sulfide form a network of cascading chemical reactions that generate radical intermediates as well as anionic and uncharged solutes, with accumulation of three major products: nitrosopersulfide (SSNO(-)), polysulfides, and dinitrososulfite [N-nitrosohydroxylamine-N-sulfonate (SULFI/NO)], each with a distinct chemical biology and in vitro and in vivo bioactivity. SSNO(-) is resistant to thiols and cyanolysis, efficiently donates both sulfane sulfur and NO, and potently lowers blood pressure. Polysulfides are both intermediates and products of SSNO(-) synthesis/decomposition, and they also decrease blood pressure and enhance arterial compliance. SULFI/NO is a weak combined NO/nitroxyl donor that releases mainly N2O on decomposition; although it affects blood pressure only mildly, it markedly increases cardiac contractility, and formation of its precursor sulfite likely contributes to NO scavenging. Our results unveil an unexpectedly rich network of coupled chemical reactions between NO and H2S/sulfide, suggesting that the bioactivity of either transmitter is governed by concomitant formation of polysulfides and anionic S/N-hybrid species. This conceptual framework would seem to offer ample opportunities for the modulation of fundamental biological processes governed by redox switching and sulfur trafficking.

Cocoa flavanol intake improves endothelial function and Framingham Risk Score in healthy men and women: a randomised, controlled, double-masked trial: the Flaviola Health Study.

Cocoa flavanol (CF) intake improves endothelial function in patients with cardiovascular risk factors and disease. We investigated the effects of CF on surrogate markers of cardiovascular health in low risk, healthy, middle-aged individuals without history, signs or symptoms of CVD. In a 1-month, open-label, one-armed pilot study, bi-daily ingestion of 450 mg of CF led to a time-dependent increase in endothelial function (measured as flow-mediated vasodilation (FMD)) that plateaued after 2 weeks. Subsequently, in a randomised, controlled, double-masked, parallel-group dietary intervention trial (Clinicaltrials.gov: NCT01799005), 100 healthy, middle-aged (35-60 years) men and women consumed either the CF-containing drink (450 mg) or a nutrient-matched CF-free control bi-daily for 1 month. The primary end point was FMD. Secondary end points included plasma lipids and blood pressure, thus enabling the calculation of Framingham Risk Scores and pulse wave velocity. At 1 month, CF increased FMD over control by 1·2 % (95 % CI 1·0, 1·4 %). CF decreased systolic and diastolic blood pressure by 4·4 mmHg (95 % CI 7·9, 0·9 mmHg) and 3·9 mmHg (95 % CI 6·7, 0·9 mmHg), pulse wave velocity by 0·4 m/s (95 % CI 0·8, 0·04 m/s), total cholesterol by 0·20 mmol/l (95 % CI 0·39, 0·01 mmol/l) and LDL-cholesterol by 0·17 mmol/l (95 % CI 0·32, 0·02 mmol/l), whereas HDL-cholesterol increased by 0·10 mmol/l (95 % CI 0·04, 0·17 mmol/l). By applying the Framingham Risk Score, CF predicted a significant lowering of 10-year risk for CHD, myocardial infarction, CVD, death from CHD and CVD. In healthy individuals, regular CF intake improved accredited cardiovascular surrogates of cardiovascular risk, demonstrating that dietary flavanols have the potential to maintain cardiovascular health even in low-risk subjects.

Association between sucrose intake and risk of overweight and obesity in a prospective sub-cohort of the European Prospective Investigation into Cancer in Norfolk (EPIC-Norfolk).

OBJECTIVE: The objective of the present study was to investigate associations between sugar intake and overweight using dietary biomarkers in the Norfolk cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk). DESIGN: Prospective cohort study. SETTING: EPIC-Norfolk in the UK, recruitment between 1993 and 1997. SUBJECTS: Men and women (n 1734) aged 39-77 years. Sucrose intake was assessed using 7 d diet diaries. Baseline spot urine samples were analysed for sucrose by GC-MS. Sucrose concentration adjusted by specific gravity was used as a biomarker for intake. Regression analyses were used to investigate associations between sucrose intake and risk of BMI>25·0 kg/m2 after three years of follow-up. RESULTS: After three years of follow-up, mean BMI was 26·8 kg/m2. Self-reported sucrose intake was significantly positively associated with the biomarker. Associations between the biomarker and BMI were positive (ß=0·25; 95 % CI 0·08, 0·43), while they were inverse when using self-reported dietary data (ß=-1·40; 95 % CI -1·81, -0·99). The age- and sex-adjusted OR for BMI>25·0 kg/m2 in participants in the fifth v. first quintile was 1·54 (95 % CI 1·12, 2·12; P trend=0·003) when using biomarker and 0·56 (95 % CI 0·40, 0·77; P trend<0·001) with self-reported dietary data. CONCLUSIONS: Our results suggest that sucrose measured by objective biomarker but not self-reported sucrose intake is positively associated with BMI. Future studies should consider the use of objective biomarkers of sucrose intake.

Human red blood cells at work: identification and visualization of erythrocytic eNOS activity in health and disease.

A nitric oxide synthase (NOS)-like activity has been demonstrated in human red blood cells (RBCs), but doubts about its functional significance, isoform identity and disease relevance remain. Using flow cytometry in combination with the nitric oxide (NO)-imaging probe DAF-FM we find that all blood cells form NO intracellularly, with a rank order of monocytes > neutrophils > lymphocytes > RBCs > platelets. The observation of a NO-related fluorescence within RBCs was unexpected given the abundance of the NO-scavenger oxyhemoglobin. Constitutive normoxic NO formation was abolished by NOS inhibition and intracellular NO scavenging, confirmed by laser-scanning microscopy and unequivocally validated by detection of the DAF-FM reaction product with NO using HPLC and LC-MS/MS. Using immunoprecipitation, ESI-MS/MS-based peptide sequencing and enzymatic assay we further demonstrate that human RBCs contain an endothelial NOS (eNOS) that converts L-(3)H-arginine to L-(3)H-citrulline in a Ca(2+)/calmodulin-dependent fashion. Moreover, in patients with coronary artery disease, red cell eNOS expression and activity are both lower than in age-matched healthy individuals and correlate with the degree of endothelial dysfunction. Thus, human RBCs constitutively produce NO under normoxic conditions via an active eNOS isoform, the activity of which is compromised in patients with coronary artery disease.

Assessment of the dietary intake of total flavan-3-ols, monomeric flavan-3-ols, proanthocyanidins and theaflavins in the European Union.

Dietary interventions with flavan-3-ols have shown beneficial effects on vascular function. The translation of these findings into the context of the health of the general public requires detailed information on habitual dietary intake. However, only limited data are currently available for European populations. Therefore, in the present study, we assessed the habitual intake of flavan-3-ol monomers, proanthocyanidins (PA) and theaflavins in the European Union (EU) and determined their main food sources using the EFSA (European Food Safety Authority) Comprehensive European Food Consumption Database. Data for adults aged 18-64 years were available from fourteen European countries, and intake was determined using the FLAVIOLA Flavanol Food Composition Database, developed for the present study and based on the latest US Department of Agriculture and Phenol-Explorer databases. The mean habitual intake of flavan-3-ol monomers, theaflavins and PA ranged from 181 mg/d (Czech Republic) to 793 mg/d (Ireland). The highest intakes of flavan-3-ol monomers and theaflavins were observed in Ireland (191/505 mg/d) and the lowest intakes in Spain (24/9 mg/d). In contrast, the daily intake of PA was highest in Spain (175 mg/d) and lowest in The Netherlands (96 mg/d). Main sources were tea (62%), pome fruits (11%), berries (3%) and cocoa products (3%). Tea was the major single contributor to monomer intake (75%), followed by pome fruits (6%). Pome fruits were also the main source of PA (28%). The present study provides important data on the population-based intake of flavanols in the EU and demonstrates that dietary intake amounts for flavan-3-ol monomers, PA and theaflavins vary significantly across European countries. The average habitual intake of flavan-3-ols is considerably below the amounts used in most dietary intervention studies.

Estimated dietary intakes and sources of flavanols in the German population (German National Nutrition Survey II).

BACKGROUND/OBJECTIVES: Data from intervention studies suggest a beneficial effect of flavanols on vascular health. However, insufficient data on their intake have delayed the assessment of their health benefits. The aim of this study was to estimate intake of flavanols and their main sources among people living in Germany. SUBJECTS/METHODS: Data from diet history interviews of the German National Nutrition Survey II for 15,371 people across Germany aged 14-80 years were analyzed. The FLAVIOLA Flavanol Food Composition Database was compiled using the latest US Department of Agriculture and Phenol-Explorer Databases and expanded to include recipes and retention factors. RESULTS: Mean intake of total flavanols, flavan-3-ol monomers, proanthocyanidins (PA), and theaflavins in Germany was 386, 120, 196, and 70 mg/day, respectively. Women had higher intakes of total flavanols (399 mg/day) than men (372 mg/day) in all age groups, with the exception of the elderly. Similar results were observed for monomers (108 mg/day for men, 131 mg/day for women) and PA (190 mg/day; 203 mg/day), although intake of theaflavins was higher in men (74 mg/day; 66 mg/day). There was an age gradient with an increase in total flavanols, monomers, and theaflavins across the age groups. The major contributor of total flavanols in all subjects was pome fruits (27%) followed by black tea (25%). CONCLUSIONS: This study demonstrated age- and sex-related variations in the intake and sources of dietary flavanols in Germany. The current analysis will provide a valuable tool in clarifying and confirming the potential health benefits of flavanols.

Reliance on self-reports and estimated food composition data in nutrition research introduces significant bias that can only be addressed with biomarkers.

The chemical composition of foods is complex, variable, and dependent on many factors. This has a major impact on nutrition research as it foundationally affects our ability to adequately assess the actual intake of nutrients and other compounds. In spite of this, accurate data on nutrient intake are key for investigating the associations and causal relationships between intake, health, and disease risk at the service of developing evidence-based dietary guidance that enables improvements in population health. Here, we exemplify the importance of this challenge by investigating the impact of food content variability on nutrition research using three bioactives as model: flavan-3-ols, (-)-epicatechin, and nitrate. Our results show that common approaches aimed at addressing the high compositional variability of even the same foods impede the accurate assessment of nutrient intake generally. This suggests that the results of many nutrition studies using food composition data are potentially unreliable and carry greater limitations than commonly appreciated, consequently resulting in dietary recommendations with significant limitations and unreliable impact on public health. Thus, current challenges related to nutrient intake assessments need to be addressed and mitigated by the development of improved dietary assessment methods involving the use of nutritional biomarkers.

Studies about the health benefits of foods or nutrients are often inconsistent. One study may find a health benefit of a particular food and may recommend that people increase their consumption of this food to reduce their disease risk. Yet another study may find the opposite. Inconsistent study results fuel confusion and frustration, and reduce trust in research. Limitations in the studies' designs are likely to be blamed for the inconsistent findings. For example, many studies rely on participants to self-report their food intake and on databases of the nutritional content of food. But people may not accurately report their food intake. Foods vary in their nutritional content, even between two items of the same food such as two apples. And how individuals metabolize foods can further affect the nutrients they receive. Nutritional biomarkers are a potential alternative to measuring dietary intake of specific nutrients. Biomarkers are compounds the body produces when it metabolizes a specific nutrient. Measuring biomarkers therefore give scientists a more accurate and unbiased assessment of nutrient intake. Ottaviani et al. conducted a study to test the differences when estimating nutrient intake using nutritional biomarkers compared with more conventional tools. They analyzed data from a nutrition study that involved over 18,000 participants. The experiments used computer modelling to assess study results using self-reported food intake in combination with food composition database information, or measures of three biomarkers estimating the intake of flavan-3-ols, epicatechin, and nitrates. The models showed that self-reported intake and food database information often led to inaccurate results that did not align well with biomarker measurements. Measuring nutritional biomarkers provides a more accurate and unbiased assessment of nutritional intake. Using these measurements instead of traditional methods for measuring nutrient intake may help increase the reliability of nutrition research. Scientists must work to identify and confirm biomarkers of nutrients to facilitate this work. Using these more precise nutrient measurements in studies may result in more consistent results. It may also lead to more trustworthy recommendations for consumers.

Carbon and nitrogen isotopic ratios of urine and faeces as novel nutritional biomarkers of meat and fish intake.

PURPOSE: Meat and fish consumption are associated with changes in the risk of chronic diseases. Intake is mainly assessed using self-reporting, as no true quantitative nutritional biomarker is available. The measurement of plasma fatty acids, often used as an alternative, is expensive and time-consuming. As meat and fish differ in their stable isotope ratios, δ(13)C and δ(15)N have been proposed as biomarkers. However, they have never been investigated in controlled human dietary intervention studies. OBJECTIVE: In a short-term feeding study, we investigated the suitability of δ(13)C and δ(15)N in blood, urine and faeces as biomarkers of meat and fish intake. METHODS: The dietary intervention study (n = 14) followed a randomised cross-over design with three eight-day dietary periods (meat, fish and half-meat-half-fish). In addition, 4 participants completed a vegetarian control period. At the end of each period, 24-h urine, fasting venous blood and faeces were collected and their δ(13)C and δ(15)N analysed. RESULTS: There was a significant difference between diets in isotope ratios in faeces and urine samples, but not in blood samples (Kruskal-Wallis test, p < 0.0001). In pairwise comparisons, δ(13)C and δ(15)N were significantly higher in urine and faecal samples following a fish diet when compared with all other diets, and significantly lower following a vegetarian diet. There was no significant difference in isotope ratio between meat and half-meat-half-fish diets for blood, urine or faecal samples. CONCLUSIONS: The results of this study show that urinary and faecal δ(13)C and δ(15)N are suitable candidate biomarkers for short-term meat and fish intake.

Intakes and sources of isoflavones, lignans, enterolignans, coumestrol and soya-containing foods in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk), from 7 d food diaries, using a newly updated database.

OBJECTIVE: A diet rich in phyto-oestrogens has been suggested to protect against a variety of common diseases but UK intake data on phyto-oestrogens or their food sources are sparse. The present study estimates the average intakes of isoflavones, lignans, enterolignans and coumestrol from 7 d food diaries and provides data on total isoflavone, lignan and phyto-oestrogen consumption by food group. DESIGN: Development of a food composition database for twelve phyto-oestrogens and analysis of soya food and phyto-oestrogen consumption in a populationbased study. SETTING: Men and women, aged 40­79 years, from the general population participating in the Norfolk arm of the European Prospective Investigation into Cancer and Nutrition (EPIC-Norfolk) between 1993 and 1997, with nutrient and food data from 7 d food diaries. SUBJECTS: A subset of 20 437 participants. RESULTS: The median daily phyto-oestrogen intake for all men was 1199 mg (interquartile range 934­1537mg; mean 1504mg, SD 1502mg) and 888mg for all women (interquartile range 710­1135 mg; mean 1205 mg, SD 1701mg). In soya consumers, median daily intakes were higher: 2861 mg in men (interquartile range 1304­7269mg; mean 5051mg, SD 5031mg) and 3142 mg in women (interquartile range 1089­7327mg; mean 5396 mg, SD 6092 mg). In both men and women, bread made the greatest contribution to phyto-oestrogen intake ­ 40?8% and 35?6%, respectively. In soya consumers, vegetable dishes and soya/goat's/sheep's milks were the main contributors ­ 45?7% and 21?3% in men and 38?4% and 33?7% in women, respectively. CONCLUSIONS: The ability to estimate phyto-oestrogen intake in Western populations more accurately will aid investigations into their suggested effects on health.

Measuring the intake of dietary bioactives: Pitfalls and how to avoid them.

Bioactives are food constituents that, while not essential to human life, can affect health. Thus, there is increased interest in developing dietary recommendations for bioactives. Such recommendations require detailed information about the long-term association between habitual intake and health at population scale, and these can only be provided by large-scale observational studies. Nutritional epidemiology relies on the accurate estimation of intake, but currently used methods, commonly based on a 2-step process involving self-reports and food composition tables, are fraught with significant challenges and are unable to estimate the systemic presence of bioactives. Intake assessments based on nutritional biomarkers can provide an advanced alternative, but there are a number of pitfalls that need to be addressed in order to obtain reliable data on intake. Using flavan-3-ols as a case study, we highlight here key challenges and how they may be avoided. Taken together, we believe that the approaches outlined in this review can be applied to a wide range of food constituents, and doing so will improve assessments of the dietary intake of bioactives.

Impact of polyphenol oxidase on the bioavailability of flavan-3-ols in fruit smoothies: a controlled, single blinded, cross-over study.

Flavan-3-ols are bioactive compounds found in a variety of fruits and vegetables (F&V) that have been linked to positive health benefits. Increasing habitual flavan-3-ol intake is challenged by the generally low consumption of F&V. While smoothies are a commonly endorsed, consumer-accepted means to increase the daily intake of these important foods, fruits used for smoothie preparation can have a high polyphenol oxidase (PPO) activity and thus potentially affect the content and bioavailability of flavan-3-ols. To assess whether or not consuming freshly prepared smoothies made with different PPO-containing fruit impacts the bioavailability of the flavan-3-ols, a controlled, single blinded and cross-over study was conducted in healthy men (n = 8) who consumed a flavan-3-ol-containing banana-based smoothie (high-PPO drink), a flavan-3-ol-containing mixed berry smoothie (low-PPO drink) and flavan-3-ols in a capsule format (control). The peak plasma concentration (Cmax) of flavan-3-ol metabolites after capsule intake was 680 ± 78 nmol L-1, which was similar to the levels detected after the intake of the low PPO drink. In contrast, the intake of the high PPO drink resulted in a Cmax of 96 ± 47 nmol L-1, 84% lower than that obtained after capsule intake. In a subsequent study (n = 11), flavan-3-ols were co-ingested with a high-PPO banana drink but contact prior to intake was prevented. In this context, plasma flavan-3-ol levels were still reduced, suggesting an effect possibly related to post-ingestion PPO activity degrading flavan-3-ols in the stomach. There was a substantial range in the PPO activity detected in 18 different fruits, vegetables and plant-derived dietary products. In conclusion, bioavailability of flavan-3-ols, and most likely other dietary polyphenol bioactives, can be reduced substantially by the co-ingestion of high PPO-containing products, the implications of which are of importance for dietary advice and food preparation both at home and in industrial settings.

5-(3',4'-Dihydroxyphenyl)-γ-Valerolactone Is a Substrate for Human Paraoxonase: A Novel Pathway in Flavan-3-ol Metabolism.

SCOPE: Dietary flavan-3-ols are known to mediate cardiovascular benefits. Currently, it is assumed that the levels of flavan-3-ol catabolites detected in humans, 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (γVL) and 5-(3',4'-dihydroxyphenyl)-γ-valeric acid (γVA), and their corresponding phase II metabolites, are determined exclusively by the action of the gut microbiome. However, a family of human proteins, paraoxonase (PON), can theoretically hydrolyze γVL metabolites into the corresponding γVAs. This study aims to determine if PON is involved in γVL and γVA metabolism in humans. METHODS AND RESULTS: A rapid conversion of γVL into γVA is detected in serum ex vivo (half-life = 9.8 ± 0.3 min) that is catalyzed by PON1 and PON3 isoforms. Phase II metabolites of γVL are also reacted with PON in serum. Following an intake of flavan-3-ol in healthy males (n = 13), the profile of γVA metabolites detected is consistent with that predicted from the reactivity of γVL metabolites with PON in serum. Furthermore, common PON polymorphisms are evaluated to assess the use of γVL metabolites as biomarkers of flavan-3-ol intake. CONCLUSION: PONs are involved in flavan-3-ol metabolic pathway in humans. PON polymorphisms have a minor contribution to inter-individual differences in the levels of γVL metabolites, without affecting their use as a nutritional biomarker.

Nutritional biomarkers for objective dietary assessment.

The accurate assessment of dietary exposure is important in investigating associations between diet and disease. Research in nutritional epidemiology, which has resulted in a large amount of information on associations between diet and chronic diseases in the last decade, relies on accurate assessment methods to identify these associations. However, most dietary assessment instruments rely to some extent on self-reporting, which is prone to systematic bias affected by factors such as age, gender, social desirability and approval. Nutritional biomarkers are not affected by these and therefore provide an additional, alternative method to estimate intake. However, there are also some limitations in their application: they are affected by inter-individual variations in metabolism and other physiological factors, and they are often limited to estimating intake of specific compounds and not entire foods. It is therefore important to validate nutritional biomarkers to determine specific strengths and limitations. In this perspective paper, criteria for the validation of nutritional markers and future developments are discussed.